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Neurobiology of pain

Updated: Jul 11, 2021

Curriculum 3.1.5


Describe the anatomy of the peripheral and central nociceptive pathways in the somatosensory system.


NB: The 'somatosensory' system is part of the sensory nervous system. It is a complex system of sensory neutrons and neural pathways that responds to changes at the surface, or inside the body.




- Nociceptor activation occurs in the periphery

- Adelta fibres (thinly myelinated) and C fibres (unmyelinated)

- Cell body is in the dorsal root ganglion (DRG)

- Noxious stimuli activates receptors from these nociceptors

- The stimuli causes these receptors to open leading to influx of Ca+ and Na+

- This lowers activation threshold and axon fires

(Other things around the damage cause this to lower also - e.g. tissue damage and inflammatory soup)



(Image - for example - one type of trigger opens this one type of channel causing depolarisation)

- Abeta fibres are fastest (A comes first!) - but Adelta are tastest noxious stimuli messengers with acute/sharp pain. C fibres mediate 'second' wave of delayed, diffuse, dull pain.

- Conduction of the action potential occurs via voltage-gated Na+ and Ca+ channels

(For example, thought there are more of these Ca channels in chronic pain - target of gabapentin/pregabalin)


- These Aδ and C fibres initially travel up or down for 1-2 vertebral levels in Lissauer's tract before synapsing with second order neurons in the DRG.

- When these action potentials arrive, depolarisation leads to activation of N-type calcium channels and this causes release of excitatory neurotransmitters such as substance P and glutamate


- Glutamate and Substance P trigger excitatory postsynaptic currents in the second-order neutrons in the dorsal horn

- This causes firing of the second order neuron

(Glutamate and substance P also affect glial cells. Glia are thought to play a role in pain enhancement)

- In the dorsal horn, primary nociceptor afferent nerve fibres synapse into specific laminae

- Mainly primary afferent nerve fibres innervate into Rexed's laminae 2 (substanstia gelatinous) and 5 (nucleus proprius).

- Spinal cord neurons in lamina 1 and 2 are generally responsive to noxious stimuli, whereas neutrons in lamina 3-4 are responsive to non-noxious stimuli (ABeta).

- Neurons in lamina 5 receive non-noxious AND noxious inputs via Aδ/Aβ inputs

- These ones in 5 are referred to as 'Wide dynamic range (WDR)' neurons because they respond to a wide amount of intensities

- 5 is where visceral inputs also come in. This convergence of somatic and visceral may explain referred pain.


- Second order neutrons then cross the spinal cord and ascend in the spinothalamic tract to the thalamus.

- In the thalamus, there is a third-order neuron where a synapse occurs

(Explains why thalamic strokes can lead to pain without involvement of messages from the spinothalamic pathway).


Remember:

- In the face things are a little different. Noxious stimuli are transmitted through nerve cells in the trigeminal ganglion and cranial nuclei 7, 9, and 10.

- These then travel to the medulla, cross the midline, and ascend to the thalamic nerve cells on the contralateral side.


Perception:

- In the thalamic nuclei, third order neurons conduct impulses to the somatosensory cortices.


- The thalamus also receives normal sensory stimuli - so can assimilate the information to give an idea of location and intensity.

- The thalamus also sends messages to the limbic (a group of subcortical structures (such as the hypothalamus, the hippocampus, and the amygdala) of the brain that are concerned especially with emotion and motivation) structures - the anterior cingulate cortex and insula - where emotional and cognitive components are processed


Modulation:

Three main types to remember: segmental inhibition, endogenous opioid system, descending inhibitory nerve system


Segmental inhibition

Melzack and Wall's 'gate theory of pain control' - Activating Abeta fibres stimulates and inhibitory nerve that inhibits synaptic transmission


Endogenous Opioid system

Endogenous opioid receptors are in lamina 2, periacqueductal grey matter, and ventral medulla.


Descending inhibitory system

Periacqueductal grey matter in upper brain stem, locus coeruleus, nucleus raphe Magnus, and nucleus retigularis gigantocellularis in rostroventral medulla, contribute to descending pathway suppression





Neurotransmitters:

Major neurotransmitters within the body are: Glutamate, GABA, noradrenaline, acetylcholine, serotonin and dopamine


GABA has an inhibitory action (usually its actions cause negative ions to Flow into a cell causing it to be more negatively charged and therefore more difficult to fire)


Glutamate is the most common excitatory transmitter


Ion channels:

Bunch of proteins in a shape to form a channel

Channel is bound in the membrane of the neutron (axolemma)

Channels are made on ribosomes around the nucleus on genetic instruction

Channels are then transported to the wall and inserted


Different factors cause an ion channel to open or close

Most only open for milliseconds. Others, such as G protein coupled receptors, can open for longer

NMDA channel is a 'memory' channel


Channels like only 'live' for a few days


Neuromatrix

Pain experience is distributed - but a basic common activation pattern will exist between people - a 'pain signature' does exist

Usually primary and secondary somatosensory cortices (limbic system, anterior cingulate and insula cortex, and sub cortically the thalamus, basal ganglia and cerebellum.

The bilateral distributed backfiring between these areas is called a 'neurotag'


Gate control theory problems:

- Focus is on the cord and not on mechanisms of the brain

- Can't explain phantom limb pain and pain in paraplegics

- Doesn't cover inflammation in tissues

- Doesn't consider the role of the immune system

 

3.1.7 Discuss current concepts of referred pain and radiation of pain


Definition

'Pain that is received in a region that has a different nerve supply to the original source of pain'


Mechanism of REFERRED pain

  • Multiple primary sensory afferents converge on a single ascending tract

  • Somatosensory cortex cannot differentiate between the multiple sites of input. These may be somatic and visceral

  • Referred pain is perceived on the SAME SIDE of the midline

  • Felt axially as a deep visceral pain or peripherally commonly in a dermatomal distribution

  • May be contiguous or separate from the nociceptive stimulus site

Mechanism of radiating pain

  • This is related to a specific spinal segment

 

Glia's role in the generation of chronic pain and pain signalling


  • Glia within the nervous system work to up or down regulate pain signalling

  • Macroglia encapsulate and surround synapses modulating synaptic communication

  • Macroglia include astrocytes, oligodendrocytes, ependymal cells, radial cells, and schwann cells (that make myelin)

  • Astrocytes are the most common glia (50%)

  • Macroglia, such as astrocytes, may themselves hypertrophy and up regulate signalling control systems leading to sensitisation

  • Microglia are immune surveillance and debris clearing cells originating from microcytes or macrophages

Activation of glia can occur through:

  • Primary afferent neurons releasing activating factors such as substance P and glutamate

  • Neuromodulators such as prostaglandins and NO can also directly activate glia cells

  • Damaged neurons release ATP/heat-shock proteins that can activate glia

Glia enhances pain signalling by:

  • Creating new connections between glial cells and activating further local glial cells

  • Release pro-inflammatory cytokines such as TNFa, IL1, IL6. These can increase release of Substance P, CGRP, and glutamate.

  • Release D-serine activating NMDA receptors

  • Increasing noradrenaline fibre bundles

  • Increase permeability of the BBB

Receptors on Glia:

  • Toll-like receptor 4, cannabinoid receptor type 2, NMDA, Mu, Kappa, Delta and OR-1

Glia has an effect on opioids:

  • Repeated opioid doses may also activate glia leading to pro inflammatory cascade

  • Increasing opioid receptors on glia, from exposure to opioids, may lead to more NO and PKC release

  • Toll-like receptor 4 is stimulated by M3G and methadone and local debris from damaged neurons

Inhibition of TLR4 leads to:

  • In animals shows reduced neuropathic pain

  • Likely naloxone works on these receptors also – not sure why

  • Lead to increased opioid analgesic effects

  • Reduces opioid tolerance

  • Reduces OIH

  • Reduces reward/dependence behaviour

  • Less withdrawal effects

  • Less resp depression


- Opioid induced tolerance, dependence, reward mechanisms

o Receptor decoupling and down regulation

o Modulation of NMDA receptors

o Reduced glutamate transporters

o NO release

o Anti-analgesia system such as CCK and dynorphin

o Glia activation – with up regulartion of receptors on Glia

- Glial modulation

o Corticosteroids are thought to play a local role

o Minocycline has been shown to reduce microglial activity by reducing NO synthesis


- Microglia play a role in initiating, sustaining, and moderating neuropathic pain

- Microglia include: Fibroblasts, astrocytes, oligodendrocites, mast cells

- Microglial cells are usually quiescent within the body. They are activated by infection immune processes and/or inflammation

- Microgliosis is where the microglia migrate and proliferate in a required area

- Nerve injury à Release of mediators nuregulin-1, MMP and CCL2 à Toll-like receptor activation à Activates microglia à Increased activation through TNFalpha and decreased inhibition of interneurons and activating more microglial cells à Increased pain

- Microglia also releasre inflammatory cytokines IL6, TNFalpha,

- Minocycline inhibits microgliosis



The overall effect of the above changes is:

· effects on receptors and channels result in

è increased opioid tolerance, opioid induced hyperalgesia and withdrawal from effect on Toll like receptors.

è Changes in neural plasticity resulting in central sensitisation.

· regulation of cytokines, chemokines, growth factors and proteases (all recognised as glial mediators) in glia which are pro-inflammatory e.g. TNF, IL6

è increased pain sensitivity

è TNF activated astrocytes in the spinal cord result in persistent mechanical allodynia

è Proteases (matrix metalloprotesase 2) released after spinal injury maintain neuropathic pain

· Modulation of excitatory and inhibitory synaptic transmission

è This happens at the spinal cord level via glial mediators (chemokines, cytokines, growth factors)

è With excitatory synaptic transmission pro-inflammatory cytokines and chemokines work on excitatory post synaptic currents (EPSC) which result in increased spontaneous frequency and amplitude of EPSC. It also results in central sensitisation via extrasynpatic pathways through TNF

è Inhibitory pathways: there is loss of inhibitory synaptic transmission resulting in central sensitisation.





Not all doom and gloom.

Glial cells also produce anti-inflammatory and anti-nociceptive mediates (IL4, IL10) which help with recovery and resolution of pain.

Minocycline is a microglial inhibitor. It has been found to potentiate acute morphine analgesia and prevents onset of enhanced pain.

NMDA antagonists inhibit microglial activation.



Inflammatory Soup

1. Bradykinin

è Potent vasodilating which results in inflammatory pain and hyperalgesia

2. Acidic environment

è Activates and sensitises nociceptors to mechanical stimuli at DRG

3. Histamine

è Released from mast cells by Substance P and CGRP causes vasodilation and odema

4. Serotonin

è Released from platelets results in direct activation of nociceptors

5. Eicosanoids

è Large family of arachidonic acid metabolites including prostaglandins, thromboxanes and leukotriene

è Reduce activation of threshold of nociceptors and increase excitability of sensory neurons

6. Cytokines

è IL 6, TNF, IL B released by a variety of cells including microglial

è Can be pro-inflammatory or anti-inflammatory

è Can excite and sensitive nociceptive afferents to thermal and mechanical stimuli

7. Nitrogen Oxide

è Released by damaged afferents and sensitise neurones augmenting pain and inflammation.

8. Excitatory Amino Acids

è Modulate nociception at DRG and presynaptic terminals of primary afferents

Others include: NGF, Proteinases, matrix metalloproteinases,


Overall these can increase sensitivity at the site of inflammation resulting in peripheral sensitisation which manifests as hyperalgesia.

Prolonged inflammation can result in transition from acute to chronic pain.


Management:

1. Pharmacotherapy to manage pain.

 use of drugs to block inflammation e.g. NSAIDS, Steroids

2. Glial cells and how using opioid can result in OIH, Dependence and withdrawal.

3. The microglial inhibitor minocycline but this has no clinical efficacy.

4. NMDA antagonists also inhibit microglial activation




Peripheral Antihyperalgeisc Mechanism.

· There are mediators that limit pain transmission and they can also be part of the inflammatory soup

1. Opioids

2. Acetylcholine

3. Gamma-aminobutyric acid

4. Somatostatin.

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